From an evolutionary perspective, contemporary diets have greatly changed from the Paleolithic diets to which our core metabolism and physiology have adapted during the long evolutionary development of homo sapiens. The difference between contemporary diets and Paleolithic diets may account for some current lifestyle-related diseases. The main difference in the diet composition is the introduction of fat-rich and sugar-rich foods replacing plant-based dietary materials. Consequently, energy-rich and nutrient-rich diets can induce a derangement of cellular function, leading to endoplasmic reticulum stress (ER stress). Under ER stress, metabolic and immune responses may induce insulin resistance through the complex intracellular signaling systems, resulting in the accumulation of uric acid. Given these considerations, we propose a dietary intervention to reduce hyperuricemia. An increased intake of plant-based foods such as vegetables and fruits for the purpose of urine alkalization, can reduce the intake of sugar-based and lipid-rich foods, thereby suppressing the de novo production of uric acid, and reducing insulin resistance caused by ER stress.

The effects of xanthine oxidase inhibitor, febuxostat, for urine urate excretion are still unclear. This study is conducted to clarify the effects of febuxostat for urine urate excretion. This is a prospective observation study (UMIN: 7350). We enrolled 16 hyperuricemic men over 20 years old whose serum uric acid levels were 8.0 mg/dL and more. The study subjects started 10 mg/day of febuxostat for two weeks, and then, the dosage was increased the dosage of 20 mg after 2weeks. They continued 20 mg/day of febuxostat for 10 weeks. We assessed the amount of urine urate excretion as (urine urate / urine creatinine), and urine urate excretion rate as ((urine urate / urine creatinine) / (serum urate / serum creatinine)) by Wilcoxon analysis. The results showed that 13 subjects were classified as low urate excretion type based on FEUA at the entry. After febuxostat treatments, FEUA decreased in 12 subjects and the amount of urine urate excretion decreased in 15 subjects. These results showed that xanthine oxidase inhibitor directly changed the urine urate excretion. We should consider the change of hyperuricemia categorization after urate lowering medication.

Hyperuricemia is considered one of the risk factors for cardiovascular and renal conditions. Several responsible genes for gout have been identified including the gene for uromodulin (UMOD). UMOD is known as the disease gene of familial juvenile hypouricemic nephropathy. On the other hand, recent GWAS revealed that UMOD is associated with hypertension. We therefore tested the hypothesis that a genetic variant of UMOD showed a significant correlation with the uric acid (UA) concentration and blood pressure (BP). We enrolled 924 consecutive patients who had consulted our hospital for lifestyle-related diseases (statistical power: 80%, significance level: 0.05). Genomic DNA was isolated from human leukocytes. Genotypes were assayed with genomic DNA for a C/T variant of UMOD (rs4293393) using the real-time PCR system and the TaqMan method. Associations between the genetic variant and serum UA (sUA), urinary UA excretion rate (uUA/uCr), fractional excretion of UA (FEUA), and BP were tested. The numbers of patients with each genotype of UMOD were as follows (CC, CT, and TT): 2, 72, and 850 patients, respectively. Accordingly, data were compared by ANOVA between the CC/CT group (74 patients) and TT group (850 patients). The sUA levels (mg/dL) were as follows: CC/CT, 4.74±1.45; TT, 5.23±1.53 (p=0.009). Thus, it was revealed that sUA is significantly higher among cases of T allele homozygotes. Other results of measurements were as follows: uUA/uCr (rate): CC/CT, 0.55±0.15; TT, 0.56±0.20 (p=0.59); FEUA (%): CC/CT, 10.2±8.8; TT, 8.2±3.6 (p=0.0028); SBP (mmHg): CC/CT, 138±21; TT, 146±24 (p=0.012); DBP (mmHg): CC/CT, 82±15; TT, 86±15 (p=0.014). The serum uric acid concentration is associated with genetic variation of UMOD, and patients with genetic variation of high serum uric acid have a high blood pressure. Thus, from the viewpoint of the Mendelian randomization theory, the high serum uric acid state may have a significant impact on blood pressure elevation.

The number of patients with gout in Japan increased fourfold in total and fivefold for men in the 30-year period after 1986, which was reported by the Comprehensive Survey of Living Conditions. Since this survey was based on self-reporting by residents, the results were compared with those of a different database. Thus, the rate of hospital visits due to gout in 2013 and 2016 based on the Comprehensive Survey of Living Conditions was compared with the prevalence of gout reported from the database of health insurance claims (2010-2014), with gout diagnosed by physicians. The results were comparable. Therefore, the trend in the number of gout patients reported by the Comprehensive Survey of Living Conditions was considered to reflect real conditions. The increase in the number of gout patients may be due to the increase in the aged population in Japan because the prevalence of gout increased with age in both databases, peaking in the 60s and 70s. Furthermore, the prevalence of gout in men has been continuing to increase in aged people, contributing to the rise in the number of gout patients. A further increase in the number of gout patients in the future is anticipated since it is estimated that the rise in the number of aged people will continue, and peak in 2042.

Aim: The number of patients with hyperuricemia has steadily risen every year. However, it remains unclear whether the prevalence of urinary stones with uric acid (UA) origin is on the same trend. Therefore, we carried out a survey on UA stones in outpatients with urolithiasis.

Methods: A retrospective survey was performed in a single municipal hospital. We enrolled a total of 312 patients diagnosed with urolithiasis during the 8 years observation period. All urinary stones underwent chemical component analysis and were divided into two groups: stones of UA component (UA group), and stones of non-UA component (non-UA group).

Results: Component analysis revealed the following; calcium oxalate stones 45.5% (n = 142), calcium phosphate stones 1.9% (n = 6), mixed stones without UA component 46.2% (n = 144), magnesium ammonium phosphate stones 1.6% (n = 5), ammonium urate stones 0.32% (n = 1), pure UA stones 2.6% (n = 8) and mixed UA stones 1.9% (n = 6). Stones with UA origin account for 4.5% (n = 14). Urinary pH was lower in the UA vs. the non-UA group (5.6 ± 0.6 vs. 6.5 ± 0.7, p < 0.01). Furthermore, HbA1c and age were higher in the UA vs. the non-UA group.A male patient in the UA group showed substantially low serum UA level (2.5 mg/dL) with multiple bladder stones, casting a suspicion of hereditary renal hypouricemia.

Conclusion: Calcium oxalate and mixed stones constitute approximately 90%. The prevalence of UA stones was 4.5%. The rate appears to remain unchanged over a past decade in Japan.

In gouty arthritis, monosodium urate (MSU) crystal deposition has been reported to decrease due to treatment for hyperuricemia; however, the association with synovial hypertrophy has not been clarified.

Therefore, we compared changes after treatment in synovial hyperplasia with US in 11 patients receiving stable uric acid-lowering drug dosages.

As a result of comparison, 8 patients showed improvement in synovial hypertrophy and a decrease in MSU crystal deposition. Compared with cases without improvement, the disease duration was shorter and the duration of treatment and period since the last gout attack tended to be longer.

Synovial hypertrophy resulting from gout attacks, like other forms of chronic arthritis, improves with treatment.

Identification of crystals using compensated polarized light microscopes is the gold standard for diagnosing crystal-induced arthritis. However, practical environment of this method has been unknown in Japan. We therefore conducted a survey of 173 educational facilities certified by the Japan College of Rheumatology in 2018 to determine the current levels of awareness about this method.

One hundred-six facilities (61.3%) responded. Ninety-two (87%) orthopedic surgery departments, 57 (54%) rheumatology or internal medicine departments, 13 (12%) internal medicine or general internal medicine departments, and 11 (10%) rheumatology or orthopedic surgery departments were equipped to perform crystal identification using compensated polarized light microscopy. Eight facilities (8%) were unable to perform this procedure.

The responses showed that among the facilities surveyed, microscopic examination was performed in a laboratory at 68 (64%), outsourced by 35 (33%), and performed by the physicians themselves at eight (8%). We contacted the facilities using compensated polarized light microscopy for details and found that all of them were using polarizing plates (a polarizer and analyzer with a built-in 90° rotatable λ-plate) instead of compensated microscopes.

No compensated polarizing light microscopes are used in Japan. There may thus be ample room for optimizing microscopic synovial fluid crystal examination in Japan.

Background: Evidence has emerged that SGLT2 inhibitors provide cardiorenal protective effects in type 2 diabetics. The mechanisms are multifactorial, but uric-acid (UA) lowering effect may be involved at least in part.

Subjects & Methods: The present study focused on changes in clinical parameters including serum UA concentration in 90 type-2 diabetics treated with SGLT2 inhibitors for a long period of time.

Results: SGLT2 inhibitors improve diabetes-related parameters such as postprandial plasma glucose concentration, HbA1c, 1,5-AG, blood pressure, body weight, BMI, and triglyceride. Furthermore, lowering of serum UA level started at 4 weeks of treatment with SGLT2 inhibitors and the effects remained constant for a period of over 48 weeks. Decrease in serum UA level was positively correlated with the increased glycosuria, which was associated with an increase in fractional excretion of urinary UA (FEUA). Urinary albumin-creatinine ratio (ACR) was normalized in a considerable number of patients, suggesting a reno-protective effect of SGLT2 inhibitors. Comparisons of individual parameters among groups given 6 different SGLT2 inhibitors showed no specific differences, suggesting that the pharmacological effects elicited by these drugs were regarded as so-called “the Class Effect”. The benefit of SGLT2 inhibitors on the prevention of gout is yet unknown.

Conclusion: SGLT2 inhibitors exert long-term serum UA lowering effect in association with increased urinary glucose and UA excretion. Whether this effect is beneficial in diabetics with hyperuricemia is still a matter for debate.

Here that was we report on a 68-year-old Japanese woman with Type 2 diabetes poorly controlled, who developed hyperuricemia after the daily use of canagliflozin. In addition to sitagliptin (50mg) and glimepiride (1mg), the level of uric acid began to increase approximately 7 months after starting the additional medication of canagliflozin (100mg). Furthermore, hyperuricemia continued for ten months and the excretion of ketone bodies increased. At that time, she was ingesting two to three liters of water a day and producing about two liters of urine. Improvement in urinary ketone bodies was noted with the suspension of canagliflozin, and hyperuricemia reappeared after tohoglifrozin was started. Normalization of uric acid and ketone bodies was observed along with a hypoglycemic effect by changing the SGLT2 inhibitor every other day. Although the cause is not clear, it should be considered that abnormalities in GLUT9 isoform 2, URAT1, or other transporters caused the increased reabsorption of uric acid. We should therefore be careful about using SGLT2 inhibitors due to not only a possible decrease in uric acid levels but also the rare occurrence of hyperuricemia.